M.A. Shullo

Persistent strong anti-HLA antibody at high titer is complement binding and associated with increased risk of antibody-mediated rejection in heart transplant recipients

BACKGROUND Sensitized heart transplant candidates are evaluated for donor-specific anti-HLA IgG antibody (DSA) by Luminex single-antigen bead (SAB) testing (SAB-IgG) to determine donor suitability and help predict a positive complement-dependent cytotoxicity crossmatch (CDC-XM) by virtual crossmatching (VXM). However, SAB testing used for VXM does not correlate perfectly with CDC-XM results and individual transplant programs have center-specific permissible thresholds to predict crossmatch positivity. A novel Luminex SAB-based assay detecting C1q-binding HLA antibodies (SAB-C1q) contributes functional information to SAB testing, but the relationship between SAB strength and complement-binding ability is unclear. METHODS In this retrospective study, we identified 15 pediatric and adult heart allograft candidates with calculated panel-reactive antibody (cPRA) >50% by SAB-IgG and compared conventional SAB-IgG results with SAB-C1q testing. RESULTS Pre- and post-transplant DSA by SAB-C1q correlated with DSA by SAB-IgG and also with CDC-XM results and early post-transplant endomyocardial biopsy findings. Individual HLA antibodies by SAB-IgG in undiluted sera correlated poorly with SAB-C1q; however, when sera were diluted 1:16, SAB-IgG results were well correlated with SAB-C1q. In some sera, HLA antibodies with low mean fluorescent intensity (MFI) by SAB-IgG exhibited high SAB-C1q MFIs for the same HLA antigens. Diluting or heat-treating these sera increased SAB-IgG MFI, consistent with SAB-C1q results. In 13 recipients, SAB-C1q-positive DSA was associated with positive CDC-XM and with early clinical post-transplant antibody-mediated rejection (cAMR). CONCLUSIONS Risk assessment for positive CDC-XM and early cAMR in sensitized heart allograft recipients are correlated with SAB-C1q reactivity.

Blood Pressure Control in Continuous Flow Left Ventricular Assist Devices: Efficacy and Impact on Adverse Events

BACKGROUND Continuous flow (CF) left ventricular assist devices (LVAD) are afterload sensitive and therefore pump performance is affected by hypertension. In addition, poorly controlled hypertension may increase the risk of aortic insufficiency (AI) and stroke. Blood pressure regimens after CF LVAD have not been studied and their impact on rates of AI and stroke are unknown. METHODS Patients who had CF LVAD at a single center and were supported greater than 30 days were included. Blood pressure was monitored at home by Doppler. Outpatient management of blood pressure was conducted according to a predefined institutional protocol (target mean arterial pressure ≤ 80 mm Hg). RESULTS A total of 96 patients were included. At the end of follow-up, 25 patients were not on an antihypertensive drug, of these 9 died. Of the 74% receiving antihypertensives, 54% required 1 medication, 34% were on 2, 10% were on 3, and 3% were on 4 or more. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (85% of patients on an antihypertensive) and beta blockers (30%) were the most commonly prescribed medications. There was a significantly higher neurologic event rate in those on no antihypertensives compared with those on antihypertensives (p = 0.009). Only 3% of patients with no or mild AI at baseline progressed to develop moderate or greater AI after a mean of 201 days of follow-up. CONCLUSIONS Blood pressure control can be achieved in patients with CF LVADs, with the majority of patients requiring only 1 or 2 antihypertensives.

Heart transplantation for adults with congenital heart disease: results in the modern era.

BACKGROUND Heart transplantation in adults with congenital heart disease (CHD) has historically been associated with sub-optimal survival compared with other indications for transplantation. The purpose of this study was to evaluate survival outcomes after heart transplantation in a contemporary cohort of adults with CHD and to identify risk factors for mortality that may help guide recipient and donor selection. METHODS We performed a retrospective analysis of our adult heart transplant database, from January 2001 to February 2011, identifying 19 patients who underwent transplantation for CHD. These patients were compared with a control group of 428 patients who underwent transplantation for indications other than CHD. Kaplan-Meier survival analysis and Cox regression modeling were performed. RESULTS The mean age for the CHD group was 39.4 ± 13 years vs 54.7 ± 12 years (p < 0.001). There was no significant difference in survival (CHD vs control) at 30 days (89% vs 92%, p = 0.5567), 1 year (84% vs 86%, p = 0.6976) or 5 years (70% vs 72%, p = 0.8478). The only significant predictor of death in the CHD group was donor organ ischemic time >4 hours (HR 13.26, 95% CI 1.3 to 132.2, p = 0.028). There was no significant correlation with recipient age, history of failed Fontan surgery, pre-operative ventilator use, donor:recipient weight ratio <0.8, donor:recipient CMV mismatch, model for end-stage liver disease (MELD) score or percent reactive antibody >10%. CONCLUSIONS In the modern era, with careful donor and recipient selection, adults with CHD have excellent early and mid-term survival after heart transplantation, rivaling that of recipients with other indications for transplantation.

Alemtuzumab Induction Prior to Cardiac Transplantation with Lower Intensity Maintenance Immunosuppression: One-Year Outcomes

Induction therapy with alemtuzumab (C‐1H) prior to cardiac transplantation (CTX) may allow for lower intensity maintenance immunosuppression. This is a retrospective study of patients who underwent CTX at a single institution from January 2001 until April 2009 and received no induction versus induction with C‐1H on a background of tacrolimus and mycophenolate. Those with C‐1H received dose‐reduced calcineurin inhibitor and no steroids. A total of 220 patients were included, 110 received C‐1H and 110 received no induction. Recipient baseline characteristics, donor age and gender were not different between the two groups. Mean tacrolimus levels (ng/mL) for C‐1H versus no induction: months 1–3 (8.5 vs. 12.9), month 4–6 (10.2 vs. 13.0), month 7–9 (10.2 vs. 11.9) and month 10–12 (9.9 vs. 11.3) were all significantly lower for the C‐1H group, p < 0.001. There were no differences between the C‐1H and no induction groups at 12 months for overall survival 85.1% versus 93.6% p = 0.09, but freedom from significant rejection was significantly higher for the C‐1H group, 84.5% versus 51.6%, p < 0.0001. In conclusion, induction therapy after CTX with C‐1H results in a similar 12 month survival, but a greater freedom from rejection despite lower calcineurin levels and without the use of steroids.

Generic maintenance immunosuppression in solid organ transplant recipients.

Survival after solid organ transplantation has increased in the era of tacrolimus and mycophenolate. This increased survival could be due in part to the broad clinical use of these potent and specific agents for maintenance immunosuppression. These drugs have enhanced specificity and potency for T and B lymphocytes compared with their predecessors, cyclosporine and azathioprine. Between 2008 and 2010, the United States Food and Drug Administration approved several generic formulations of both tacrolimus and mycophenolate mofetil. Deciding whether generic products can be safely substituted for the innovator product is a clinical dilemma similar to that which occurred when generic formulations of cyclosporine became available. We describe the concerns regarding generic immunosuppression use, summarize expert opinion and consensus statements in transplantation, analyze the potential impact of generic substitution, and provide estimates of populations affected based on generic drug market penetration. Formulary considerations such as cost, availability, and potential drug ordering and drug selection errors are described, and transplant coordinator and patient perspectives are reviewed. Finally, general recommendations about the use of generic maintenance immunosuppression in solid organ transplant recipients are provided. Although more research is needed to confirm clinical and therapeutic equivalence and pharmacoeconomic benefit, generic immuno‐suppressants can be safely substituted for innovator products as long as patients consistently receive the same product, patients and clinicians are aware of when substitutions occur, and enhanced therapeutic drug monitoring is provided during the transition.

Limited tolerability of levofloxacin and pyrazinamide for multidrug-resistant tuberculosis prophylaxis in a solid organ transplant population

Study Objective. To determine the long‐term tolerability of prophylactic administration of pyrazinamide and levofloxacin in patients possibly exposed to multidrug‐resistant tuberculosis (MDRTB) after undergoing solid organ transplantation.

Impact of Renal Function Before Mechanical Circulatory Support on Posttransplant Renal Outcomes

BACKGROUND Renal dysfunction is common before mechanical circulatory support (MCS). Mechanical circulatory support frequently improves renal function, but the impact of pre-MCS renal dysfunction on renal function after cardiac transplantation (CTX) is unknown. METHODS Patients with MCS from January 1995 until April 2008 at a single center were included if their MCS duration was at least 60 days and they underwent successful CTX. Patients were followed for 1 year after CTX. RESULTS A total of 116 patients were included in the study. Mechanical circulatory support was biventricular assist device in 28% and left ventricular assist device in 72% (continuous flow left ventricular assist device, 14%). Mean duration of MCS was 124 days. Patients were grouped according to tertiles of pre-MCS creatinine clearance (CrCl): group 1, CrCl less than 45 mL/min; group 2, CrCl between 45 and 65 mL/min inclusive; and group 3, CrCl more than 65 mL/min. Group 3 had the best renal outcomes both after MCS and 1 year after CTX. Regardless of group, patients who had a CrCl of at least 60 mL/min before CTX had similar 1-year posttransplant CrCl (55 versus 53 versus 56 mL/min for groups 1 through 3, respectively; not significantly different). However, the ability to achieve this level of renal function after MCS was less likely in those with the worst renal function before the initiation of MCS (53% versus 74% versus 90% for groups 1 through 3, respectively; p=0.001). CONCLUSIONS The use of MCS leads to improvements in renal function in patients after MCS. However, the renal outcomes after CTX seem to be more dependent on the level of renal function achieved during MCS than on the level of renal function before MCS.

Optical coherence tomography for characterization of cardiac allograft vasculopathy after heart transplantation (OCTCAV study)

BACKGROUND Optical coherence tomography (OCT) is a novel intravascular imaging modality with excellent spatial resolution. This study explored the utility of OCT in cardiac transplantation for the detection and characterization of early changes associated with coronary allograft vasculopathy (CAV). METHODS Fifteen consecutive patients, 1 to 4 years after transplant with no angiographic evidence of CAV, underwent successful OCT imaging using the Fourier-domain OCT system (C7-XR, St. Jude Medical, St. Paul, MN) in the left anterior descending artery. Analysis included measurements of the lumen, intima, and media layers, and characterization of atherosclerotic plaques. Patients were stratified by intima-to-media (I/M) ratio and classified as normal (≤1) or abnormal (>1). RESULTS Patients were a mean of 2.8 years after transplant, 58 years old, and 92% were men. OCT imaging revealed 8 of 15 patients had intimal hyperplasia with an I/M ratio >1. Comparing those with I/M ratio of ≤1 and >1, the median (interquartile range) intimal thickness was greater (75 [70-101] vs 206 [97-269]μm, p = 0.03), whereas the media thickness was no different (72 [70-103] vs 94 [73-113]μm, p = 0.53). In addition, 7 of 15 patients had lipid-rich or calcified atherosclerotic plaques. CONCLUSIONS OCT provides high-resolution quantitative imaging of the coronary arteries and its use allows for detailed assessment of the coronary artery wall and early morphologic changes that occur after cardiac transplantation. The clinical predictive value of these OCT-derived measurements remains to be determined.

Aggressive steroid weaning after cardiac transplantation is possible without the additional risk of significant rejection.

Abstract: Background:  Chronic steroid use after cardiac transplantation (CTX) is accompanied by co‐morbidities that are dependent on length of exposure.

Obese patients and mechanical circulatory support: weight loss, adverse events, and outcomes.

BACKGROUND Obesity and heart failure are increasingly common, but the outcomes, weight changes, and adverse events of patients with advanced heart failure and obesity on mechanical support is not well described. METHODS We retrospectively reviewed all non-underweight patients with durable mechanical support at a single institution from January 2000 until December 2008 and compared outcomes, weight change, and Interagency Registry for Mechanically Assisted Circulatory Support-defined adverse events between obese and nonobese patients. RESULTS A total of 169 patients were included; 113 (67%) nonobese and 56 (33%) obese. Baseline characteristics, pump types, and implant duration were similar for both populations with the exception of more diabetes (61% vs 26%, p < 0.0001) and hypertension (61% vs 42%, p = 0.019) in the obese. Outcomes on mechanical support at 6 months were not different between groups. There was no significant difference between the nonobese and obese groups in the change in body mass index (-0.3 vs -1.0 mg/m(2), p = 0.29) over the duration of support. Obese patients, as compared with the nonobese, had higher incidence rates of sepsis (64.5% vs 34.7%, respectively, p = 0.006) and reoperation for infectious complications (34.2% vs 13.3%, respectively, p = 0.014). Obese patients also had a higher cumulative incidence of sepsis and reoperation for infection. Two-year posttransplant outcomes were not different in the obese and nonobese. CONCLUSIONS Obese patients have similar outcomes on mechanical support, but at the cost of a higher cumulative incidence of sepsis and reoperations for infection; however, obese patients lose little weight while on mechanical support.